The 3,4-Methylene-dioxymethamphetamine (MDMA, 'Ecstasy'') is an illicit amphetamine analog that is increasing in popularity in the United States and abroad. In addition to its abuse potential, MDMA is well documented as a potent and selective serotonin neurotoxin in animals. A growing body of evidence indicates that human MDMA users are also susceptible to MDMA-induced serotonin neurotoxicity. Although functional sequelae of MDMA-induced serotonin neurotoxicity appear to be subtle, a number of laboratories have documented abnormalities in memory and other cognitive processes in MDMA users compared to matched control groups. Since it is known that neurons involved in cognitive processes decrease with aging (e.g., catecholaminergic and cholinergic neurons), there is concern that MDMA users may be at risk for developing clinically significant cognitive abnormalities as they age. The overall goal of this revised competing renewal application is to determine if pharmacological and physiological challenges that are intended to simulate selected features of aging (i.e., loss of catecholaminergic/cholinergic function and/or sleep continuity) can be used to better detect and characterize possible detrimental effects of MDMA neurotoxicity upon cognitive processes in humans. The hypothesis to be tested is that MDMA-induced brain serotonergic injury will render MDMA users more susceptible to cognitive deficits associated with disruption of catecholaminergic and cholinergic neurotransmission and sleep continuity. The Specific Aims of the project are: 1) To determine whether or not MDMA users, compared to matched controls, are more susceptible to the disruptive effects of the catecholamine synthesis inhibitor, alpha-methyl-para-tyrosine (AMPE), on cognitive processes; V To determine if MDMA users, compared to matched controls, are more susceptible to the disruptive effects of the cholinergic antagonist, scopolamine, on cognitive processes; 3) To determine whether or not sleep deprivation, a naturalistic physiological challenge that is known to lead to deficits in cognition (and which is common in elderly populations), produces more profound effects on cognition in MDMA users compared to matched controls; and 4) To determine whether there is a relationship between cognitive deficits in MDMA users and the level of CSF 5-hydroxyindoleacetic acid, a validated measure of MDMA-induced brain serotonin neurotoxicity. The proposed studies hold promise for improving our understanding of the functional consequences of MDMA-induced serotonin neurotoxicity in humans, and should advance knowledge regarding the role of brain serotonin and other neurotransmitter systems in cognition.